Background: Sigma receptors, N-methyl-D-aspartate (NMDA) antagonist, and modulators of intracellular calcium may be useful for seizure control. Therefore, we aimed to evaluate the antiepileptic effects of opipramol, a sigma receptor agonist, against pentylenetetrazole (PTZ)-induced seizures in mice and assess ketamine and caffeine interaction with the antiepileptic effects of opipramol.Methods: PTZ (100 mg/kg) was used for the induction of seizure in 72 male albino Swiss strain of mice (n=8). Opipramole (10, 20, and 50 mg/kg), ketamine (50 mg/kg), caffeine (200 mg/kg), opipramole (20 mg/kg) plus ketamine (50 mg/kg), opipramole (20 mg/kg) plus caffeine (200 mg/kg), diazepam (5 mg/kg as a positive control), and the vehicle were administered interaperitoneally 30 minutes before the injection of PTZ. The latency was recorded for the clonic, tonic-clonic seizures, and death of animals after the injection of PTZ. Kruskal-Wallis test followed by Dunn’s test was used for the analysis of data. Statistical analysis was performed with the SPSS software version 23.0 and P<0.05 was considered as the significant level. Results: Opipramol (20 mg/kg) increased the latency for the PTZ-induced clonic (44%, P=0.021) and tonic-clonic (130.80%, P=0.043) seizures compared with the vehicle-treated group. Animals treated with opipramol (20 mg/kg) plus caffeine (200 mg/kg) had a significantly higher onset of PTZ-induced clonic and tonic-clonic seizures compared with the control (P=0.046 and <0.001, respectively). Ketamine combined with opipramol increased the onset of tonic-clonic seizure compared with the vehicle-treated groups (P<0.001).Conclusion: Opipramol attenuated the seizures induced by the PTZ. Ketamine and caffeine had no effect on the anticonvulsant activity of opipramol.